Molecular Modelling of Human Multidrug Resistance Protein 5 (ABCC5)

Natesh Singh

doi:10.4236/jbpc.2016.73006

Abstract

Multidrug resistance protein 5 (MRP5/ABCC5) is a 161 kDa member of the super family of ATP- binding cassette (ABC) superfamily of transmembrane transporters that is clinically relevant for its ability to confer multidrug resistance by actively e?uxing anticancer drugs. ABCC5 has also been identified as an efflux transporter of cGMP (cyclic guanosine monophosphate). Elevated intracellular levels of cGMP in cancer cells have been implicated in several clinical studies, that may induce apoptosis, and as a result many different cancer cells seem to overcome this deleterious effect by increased efflux of cGMP through ABCC5. Thus inhibition of ABCC5 may have cytotoxic effects mediated through cGMP and it will also increase the intracellular concentration of other drugs that are aimed for the treatment of cancer which are otherwise exported out of the cells. Considering the functional importance and lack of X-ray crystal structure of ABCC5, present work was undertaken to construct 3D structure of protein using homology modeling protocol of YASARA structure (V. 16.3.28). In this study, five different ABC templates (PDB ID’s: 4F4C, 4Q9H, 4M1M, 4M2T and 4KSD) were used for homology modeling. Five models were constructed on each template and a hybrid model was built using all five templates. All models were refined and ranked as per their overall Z-score. The top ranked ABBC5 model was based on template 4Q9H that had 91.2% of residues in allowed regions as revealed by PROCHECK-NMR and the QMEAN score was 0.54 which indicated a reliable model. The results of the study and the proposed model can be further used for elucidating the structural and functional aspects of ABCC5 and to gain more insights to the molecular basis of ABCC5 inhibition through docking studies.

Highlights

ABCC5 belongs to the ATPbinding cassette (ABC) transporters, which are structurally related membrane proteins featuring intracellular motifs that exhibit ATPase activity [1]
The best homology model of ABCC5 was model number 22 (Table 1 lists all models that were built on different templates) and this model was based on crystal structure of P-glycoprotein (PDB ID: 4Q9H) of 3.4 Å (Figure 2)
The Walker A motifs consisted of a coiled loop and a short α-helix (P-loop), and the Walker B motifs were in β-sheet conformation and localized in the nucleotide binding domain (NBD)’s hydrophobic cores, which consisted of 5 parallel β-sheets and 1 anti-parallel β-sheet

Summary

Introduction

ABCC5 belongs to the ABC transporters, which are structurally related membrane proteins featuring intracellular motifs that exhibit ATPase activity [1]. This nucleotide binding domain (NBD), which contains the Walker A and Walker B motifs, cleaves ATP’s terminal phosphate to energize the transport of substrate molecules against a concentration gradient. The human ABC transporter ABCC5 transports cGMP out of cells, and the increased cGMP efflux from cancer cells may be caused by an up regulation of ABCC5. Increased cGMP efflux by ABCC5 may be one mechanism whereby cancer cells can develop resistance against endogenous growth control, and against antineoplastic drugs which are substrates for ABCC5. Increased cGMP efflux by ABCC5 may be one mechanism whereby cancer cells can develop resistance against endogenous growth control, and against antineoplastic drugs which are substrates for ABCC5. cGMP regulates several apoptosis-associated genes, and intracellular elevation of cGMP concentration by inhibition of ABCC5 efflux may give cytotoxic effects [8]

Methods

Results

Conclusion